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-Lipoic Acid on Early Glomerular Injury in Diabetes Mellitus
*
Department of Medicine, Veterans Affairs Medical Center and University of
Pittsburgh, Pittsburgh, Pennsylvania.
Department of Pathology, Veterans Affairs Medical Center and University of
Pittsburgh, Pittsburgh, Pennsylvania.
Correspondence to Dr. Frederick R. DeRubertis, Department of Veterans Affairs Medical Center, University Drive C, Pittsburgh, PA 15240. Phone: 412-688-6000 x4690; Fax: 412-688-6947; E-mail: frederick.derubertis{at}med.va.gov
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-Lipoic acid (LA)
has been found to attenuate diabetic peripheral neuropathy, but its effects on
nephropathy have not been examined. In the present study, parameters of
glomerular injury were examined in streptozotocin diabetic rats after 2 mo on
unsupplemented diets and in diabetic rats that received the lowest daily dose
of dietary LA (30 mg/kg body wt), VE (100 IU/kg body wt), or vitamin C (VC; 1
g/kg body wt), which detectably increased the renal cortical content of each
antioxidant. Blood glucose values did not differ among the diabetic groups. At
2 mo, inulin clearance, urinary albumin excretion, fractional albumin
clearance, glomerular volume, and glomerular content of immunoreactive
transforming growth factor-ß (TGF-ß) and collagen 1 (IV) all
were significantly increased in unsupplemented D compared with age-matched
nondiabetic controls. With the exception of inulin clearance, LA prevented or
significantly attenuated the increase in all of these glomerular parameters in
D, as well as the increases in renal tubular cell TGF-ß seen in D. At the
dose used, VE reduced inulin clearance in D to control levels but failed to
alter any of the other indices of glomerular injury or to suppress renal
tubular cell TGF-ß in D. VC suppressed urinary albumin excretion,
fractional albumin clearance, and glomerular volume but not glomerular or
tubular TGF-ß or glomerular collagen 1 (IV) content. LA but not VE
or VC significantly increased renal cortical glutathione content in D. These
data indicate that LA is effective in the prevention of early diabetic
glomerular injury and suggest that this agent may have advantages over high
doses of either VE or VC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-tocopherol intraperitoneally at a dose sufficient to increase renal
cortical VE content and observed attenuation of glomerular hyperfiltration and
albuminuria in the STZ-diabetic rat. However, in this diabetic model, effects
of VE on nephropathy have been variable. Thus, dietary supplementation with
2000 IU VE/kg diet, a dose that also raised renal cortical VE levels, failed
to prevent increases in albumin clearance in the STZ-diabetic rat
(21), whereas low-dose dietary
VE supplementation (100 IU/kg diet) exacerbated renal injury in this
experimental model (20). The
reasons for the different renal responses to VE observed in STZ diabetes
mellitus are uncertain. The exacerbation of renal injury observed with
low-dose dietary supplementation of VE could be related to the recognized
capacity of this agent to act as a prooxidant under some conditions of
increased oxidative stress
(24). Beneficial effects on
diabetic nephropathy of VE and other antioxidants have been observed with
relatively high doses
(9,19,21,22,23).
In experimental diabetes mellitus in the case of VE and VC, these doses have
been sufficient to raise renal cortical levels of the antioxidants
(19,21),
although it has not been established that this is essential to their
renoprotective effects. Whether other antioxidants can provide more consistent
renal protection in diabetes mellitus and/or do so when used at relatively low
doses remains to be established.
-Lipoic acid (LA) is an endogenously produced coenzyme that plays an
essential role in mitochondrial dehydrogenase reactions
(25). Its properties as an
antioxidant have recently been reviewed
(25). LA or its reduced form,
dihydrolipoic acid (DHLA), quenches a number of oxygen-free radical species in
both lipid and aqueous phase, chelates transition metals, and prevents
membrane lipid peroxidation and protein damage via interactions with VC and
glutathione (25). LA
participates in the recycling of VC and VE, increases cellular levels of
glutathione, and suppresses nonenzymatic glycation
(25). Treatment with LA
reduces markers of oxidative stress in plasma of patients with diabetes
mellitus and poor glycemic control
(26). There is evidence in
both human and experimental diabetes mellitus that administration of LA
ameliorates diabetic neuropathy
(27,28,29,30).
In the STZ-diabetic rat, dose-response effects of LA have been reported on
parameters of neural injury
(27,28,30),
with benefits described in response to daily doses of LA from 25 to 100 mg/kg
body wt. Very limited data are available on the effects of LA on diabetic
nephropathy. A nonblinded study of patients with types 1 and 2 diabetes
mellitus with clinical nephropathy demonstrated a 50% reduction in proteinuria
after 3 mo of oral LA administration (300 to 600 mg/d) that was associated
with a reduction in serum malondialdehyde
(22). However, there has been
no systematic examination of LA actions on renal function or structure in
either human or experimental diabetes mellitus. Accordingly, in the current
study, we compared the effects of dietary supplementation of LA with those of
VE and VC on parameters of early glomerular injury in the STZ-diabetic rat.
Each antioxidant was used at the lowest daily oral dose that detectably
increased renal cortical levels of that agent in the diabetic animals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-tocopherol acetate, 1.36 IU/mg)/kg
diet; and group V, diabetic rats whose diet was supplemented with 400 mg/kg
LA. Each group contained eight rats. Desferrioxamine was added to drinking
water that had been supplemented with VC to prevent oxidation of ascorbate.
Desferrioxamine is poorly absorbed when administered orally. Accordingly, it
is doubtful that this agent altered cellular or plasma iron
compartmentalization or contributed to the systemic effects of VC. Rats were
started on the supplemented diets or drinking water 48 h after injection of
STZ. Nondiabetic controls and unsupplemented diabetic rats were fed standard
rat chow. Diabetic rats that received VC supplementation consumed an average
of 1 g VC/kg body wt per d. Diabetic rats that received VE supplementation
consumed an average of approximately 100 IU (77 mg) VE/kg body wt per d.
Diabetic rats that received LA supplementation consumed an average of 30 mg/kg
body wt per d. Diabetic rats that received standard rat chow consumed an
average of 5 IU VE/kg body wt per d. Standard chow does not contain added VC
or LA because rats synthesize both of these moieties. Blood glucose from tail vein samples and BP were determined at 2-wk intervals. BP was measured with an electrosphygmograph and microphone cuff (International Biomedical, Austin, TX). The week before the rats were killed, they were placed in metabolic cages and their urine was collected for 24 h for determination of inulin and albumin clearances. [14C] inulin clearance was determined in conscious, unrestrained rats with the use of a subcutaneous osmotic minipump to deliver [14C] inulin as described previously (31). An aliquot of the urine was frozen for determination of albumin and [14C] inulin. Blood was also obtained from the tail vein for determination of [14C] inulin and albumin at the conclusion of the urine collection. All rats were sacrificed 2 mo after entry into the study protocol. The kidneys were perfused free of blood in situ with ice-cold saline before resection. After weights were obtained, one kidney was fixed in buffered formalin for subsequent immunohistochemistry. The second kidney was quick-frozen in liquid N2 and stored at -80°C for immunohistochemistry and determination of VC, VE, LA, and glutathione content.
Determination of Albumin and Fractional Albumin Clearance
Albumin was determined by an enzyme-linked immunosorbent assay as described
previously (31). Rabbit
anti-rat albumin (IgG fraction) and peroxidase-conjugated rabbit anti-rat
albumin were obtained from ICN Pharmaceuticals (Aurora, OH) and diluted 10,000
and 600 times, respectively. Heat-inactivated normal rabbit serum was used as
a blocker. Standard curves were linear between 0.5 and 40 ng of albumin per
well. Addition of known standard amounts of albumin to urine from each of the
rat groups resulted in complete recovery of added albumin. Albumin and inulin
clearances were calculated, and fractional clearance of albumin was expressed
as the ratio of albumin to inulin clearance.
Immunohistochemical Staining for TGF-ß and Collagen 1
(IV)
Renal cortical sections (5 µm) for transforming growth factor-ß
(TGF-ß) staining were fixed in buffered formalin and blocked for 60 min.
They were then incubated overnight at 4°C with 50 µg/ml
affinity-purified polyclonal rabbit panspecific anti-TGF-ß antibody (R
and D Systems, Minneapolis, MN). This antibody reacts with TGF-ß1,
TGF-ß2, TGF-ß1.2, TGF-ß3, and TGF-ß5. Of these,
TGF-ß1, 2, and 3 have been reported to be produced by rat mesangial cells
(32). Frozen renal cortical
sections (5 µm) were used for assessment of collagen 1 (IV). Rabbit
anti-mouse collagen 1 (IV) antibodies were obtained from Chemicon
International, Inc. (Temecula, CA). Nonspecific staining was assessed by
replacing the primary antibody with affinity-purified, nonimmune, rabbit IgG
(R and D Systems). Sections were washed and further developed according to the
directions of the manufacturer (Dako Corporation, Carpinteria, CA) using an
LSAB2 kit that contained second antibody linked to avidin and peroxidase
conjugated to biotin. Immunohistochemical staining for TGF-ß and collagen
1 (IV) were assessed quantitatively with a SAMBA 4000 image analyzer
(Image Products International, Chantilly, VA) using specialized computer
software (Immuno-Analysis, version 1.4, Microsoft, Richmond, WA), a color
video camera, and a Compaq computer. Four to five glomeruli per rat were
assessed for area and intensity of staining as described previously
(21). Results are presented as
the labeling index, which represents the percentage of the total examined
glomerular area that stained positively. Staining intensity of positive areas
was also assessed (mean optical density). A mean quick score was then
calculated (mean optical density x labeling index) for the glomeruli
from each rat.
Glomerular Volume
Glomerular volume (VG) was determined on 32 glomeruli per group,
as previously reported
(21,31).
Briefly, VG was calculated from glomerular cross-sectional area as
determined on formalin-fixed tissue by light microscopy using a SAMBA 4000
image analyzer. The formula VG = B/k(AG)3/2,
in which AG is the cross-sectional area of the glomerulus, was used
for the calculation. B = 1.38 is the shape coefficient for spheres, and k =
1.1 is a size distribution coefficient.
Tissue sections for VG and immunohistochemistry were randomized and examined in a coded manner. Thus, the treatment groups from which the renal sections came were not known to the pathologist.
Assay of Renal Cortical Reduced Glutathione Content
Glutathione was assayed in extracts of quick-frozen renal cortex by its
ability to form a highly colored yellow anion when reacted with
5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) as described previously
(33).
Determination of Renal Cortical Antioxidant Content
Renal cortical ascorbic acid
(34), -tocopherol
(34), and LA
(35) were determined by HPLC
in extracts of renal cortex that had been quick-frozen in liquid nitrogen. For
LA, the lower limit of detection by this method in renal cortex was 0.2 ng/mg
protein (1 pmol/mg protein). Recovery of LA added to renal cortical extracts
exceeded 95%.
Statistical Analyses
Significance of differences was determined by ANOVA followed by the Fisher
multiple comparison test using Statview software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As shown in the upper panel of Figure 1, compared with values in nondiabetic rats, 24-h urinary albumin excretion (UAE) was significantly higher in diabetic rats that were receiving no supplementation and in diabetic rats that were receiving VE or VC. By contrast, supplementation with LA reduced UAE in diabetic rats to values that were not different from those in nondiabetic rats. As illustrated in the lower panel of Figure 1, fractional clearance of albumin was also significantly elevated in untreated diabetic rats and those that were receiving VE or VC compared with control values; supplementation of LA reduced fractional clearance of albumin to values that were not different from those in nondiabetic rats. Although VC failed to suppress UAE or fractional albumin clearance of diabetic rats to control levels, these indices were significantly lower in diabetic rats that were receiving VC than corresponding values in unsupplemented diabetic rats.
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As illustrated in Figure 2, VG was significantly greater in unsupplemented diabetic rats compared with values in control rats. Supplementation of diabetic rats with VC or LA reduced VG to values that were not different from those in control rats, whereas supplementation of diabetic rats with VE had no effect on VG.
|
Figures 3 and 4 illustrate the influence of antioxidant supplementation on glomerular immunoreactive TGF-ß content. Representative examples of glomerular staining for TGF-ß in renal cortical sections from each study group are shown in Figure 3, and assessment of glomerular staining by quantitative image analysis is shown in Figure 4. As assessed by quantitative analysis, the area positive for TGF-ß staining (labeling index, Figure 4) was markedly expanded in glomeruli from untreated diabetic rats compared with nondiabetic rats. Supplementation of diabetic rats with VC or VE had no effect on this parameter. However, supplementation of diabetic rats with LA markedly reduced the labeling index of glomerular immunoreactive TGF-ß to values that were not different from those in control rats. Calculated quick scores (labeling index x intensity of positive staining) gave results in the study groups analogous to those shown in Figure 4 for labeling index, as did assessment by visual inspection of representative renal cortical sections (Figure 3).
|
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Figures 5 and
6 illustrate the influence of
antioxidant supplementation on glomerular immunoreactive collagen 1
(IV) content. Representative examples of glomerular staining for collagen
1 (IV) in renal cortical sections are shown in
Figure 5, and assessment of
staining by quantitative image analysis is shown in
Figure 6. Collagen 1
(IV) staining was markedly increased in basement membrane and mesangium of
glomeruli from untreated diabetic rats compared with values in control rats as
assessed by visual inspection of representative renal cortical sections
(Figure 5) or quantitatively
from the labeling index (Figure
6). Supplementation of diabetic rats with VC or VE had no effect
on glomerular collagen 1 (IV) immunoreactivity, as shown in Figures
5 and
6. However, supplementation
with LA markedly reduced glomerular immunoreactive collagen 1 (IV) of
diabetic rats to levels that were not different from those in control rats
(Figures 5 and
6). Calculated quick scores of
glomerular collagen 1 (IV) staining gave results analogous to those
shown in Figure 6 for labeling
index.
|
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Figure 7 shows representative tubulointerstitial histology and tubuloimmunoreactive TGF-ß content in renal cortical sections of nondiabetic, untreated diabetic and LA-treated diabetic rats. The major histologic change observed in this region of the kidney in untreated diabetic rats compared with nondiabetic rats was tubular dilation. This was attenuated by LA (Figure 7) but not VC and VE (not shown). Focal areas of tubular cell atrophy and dropout were also observed in cortex from all of the diabetic groups. Interstitial inflammatory infiltrates and interstitial fibrosis (assessed by trichrome staining) were not observed in any of the study groups. Because of tubular dilation in the diabetic rats, quantitative image analysis of fixed areas of the tubulointerstitial region of the cortex, which included enlarged tubular lumens, did not accurately reflect obvious increases in immunochemical staining for TGF-ß observed in cortical tubule cells in the untreated diabetic rats compared with controls (Figure 7). Accordingly, labeling indices and mean optical densities of tubulointerstitial areas were not calculated. The tubular cell staining intensity for immunoreactive TGF-ß was graded semiquantitatively by visual inspection of cortical sections from five rats from each study group using a scale of +1 to +4, with +1 arbitrarily representing TGF-ß staining intensity in tubule cells of nondiabetic rats. There was a clear increase (+3) over control in the tubular cell content of immunoreactive TGF-ß in untreated diabetes mellitus. Staining intensity for TGF-ß was reduced to control levels (+1) in LA-treated diabetic rats (Figure 7) but not in those treated with VC or VE (not shown).
|
Focal increases in tubular basement membrane staining intensity for immunoreactive collagen IV were also observed in the renal cortex of the diabetic groups, as assessed by visual inspection. However, these apparent increases occurred predominantly in areas of tubular cell atrophy or dropout and thus may have been secondary to basement membrane collapse or contraction after cell loss.
As illustrated in Figure 8, VC or VE content of renal cortex of diabetic rats that were receiving no antioxidant supplementation were 20 and 35% lower, respectively, than corresponding values in nondiabetic rats. However, these differences were not statistically significant. LA was not detectable in renal cortex from control rats, untreated diabetic rats, or diabetic rats that received VC or VE (not shown). The lower limit of detection of LA in renal cortical extracts by the methodology used in the current study was 0.2 ng/mg protein. Thus, in all of the foregoing study groups, renal cortical content was below this level. Supplementation of diabetic rats with VC significantly increased renal cortical VC but not VE content. Conversely, supplementation of diabetic rats with VE significantly increased VE but not VC content of renal cortex. In diabetic rats that received LA supplementation (30 mg/kg body wt per d), renal cortical LA content was 5.6 ± 0.6 ng (27 ± 3 pmol)/mg protein. Given the sensitivity of the LA assay used (0.2 ng/mg protein), failure to detect increases in renal cortical LA in diabetic rats supplemented with 15 mg/kg body wt per d suggests that LA content of this tissue, at least in diabetes mellitus, does not increase linearly with dietary consumption. Renal cortical VC or VE content of diabetic rats that received LA supplementation did not differ from corresponding values in untreated diabetic rats.
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As illustrated in Figure 9, renal cortical content of reduced glutathione was not different in unsupplemented diabetic rats compared with the value in nondiabetic rats. Supplementation of diabetic rats with VC or VE had no significant effect on renal cortical glutathione content. However, renal cortical glutathione was clearly higher in the diabetic rats that received LA supplementation compared with values in unsupplemented diabetic rats or those receiving VE or VC supplementation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 (IV) observed in the untreated STZ-diabetic
rat all were absent or markedly attenuated in diabetic rats that were treated
with LA. At the doses used in the current study, neither LA nor VC prevented
glomerular hyperfiltration in the diabetic rats, whereas both of these agents
suppressed albuminuria. By contrast, VE suppressed inulin clearance in the
diabetic rats to control values but did not reduce UAE or fractional albumin
clearance in the diabetic rats. Consistent with earlier interventional studies
in the STZ-diabetic rat
(20,36),
the current results with LA demonstrate that albuminuria in diabetes mellitus
can be reduced despite persistent glomerular hyperfiltration. LA but not VC or
VE also reduced cortical tubular cell content of TGF-ß in the diabetic
rats. To the extent that increases in tubular TGF-ß contribute to the
tubulointerstitial fibrosis observed later (4 to 6 mo) in the course of STZ
diabetes mellitus in the rat
(37), LA may also attenuate
diabetic injury in this region of the kidney. The mechanisms by which dietary supplementation of LA attenuates renal injury in diabetes mellitus is not established by the current studies. LA and DHLA participate in the recycling of VC and VE (25). Renal cortical LA content was increased in the rats that received LA supplementation. However, renal cortical VC and VE levels in diabetic rats did not differ from corresponding values in untreated diabetic rats. Accordingly, the effects of LA were not attributable to an enhancement of VC or VE availability in the renal cortex of the diabetic rats. As noted above, LA is converted to the dithiol DHLA intracellularly (25). The latter is an especially powerful antioxidant that, along with LA, increases cellular glutathione levels in vitro and in vivo (38,39). LA supplementation in the present study clearly increased glutathione levels in renal cortex of the diabetic rats, which is consistent with previously reported effects of LA in other tissues (38). By contrast to LA, at the doses tested in the present study, neither VC nor VE supplementation altered renal cortical glutathione content. Thus, increases in renal cortical LA and glutathione content were correlated with reductions in UAE, VG, glomerular and tubular content of TGF-ß, and glomerular collagen IV in the diabetic rats but not with reductions in either renal mass or GFR. Of note, improvement of parameters of peripheral nerve injury in the STZ-diabetic rat model in response to LA is also associated with an increase in the glutathione content of this tissue (28), suggesting that this intracellular antioxidant moiety may participate in the protection of both the nerve and the kidney from injury in diabetes mellitus.
Glomerular TGF-ß is increased in both human and experimental diabetes
mellitus, and this prosclerotic cytokine has been implicated as a major
mediator of glomerular mesangial expansion in diabetic nephropathy
(40,41,42,43).
Similar to in vivo results in experimental diabetes mellitus, in
vitro studies in cultured glomerular mesangial cells (MC) have
demonstrated that several structurally distinct antioxidants, including
-to-copherol, n-acetyl cysteine, and taurine, can suppress increases in
active and latent TGF-ß and the subsequent increases in matrix protein
synthesis induced by culture of MC with high concentrations of glucose,
angiotensin II, or thromboxane
(44,45).
These observations have implicated oxidative mechanisms in the increases in
TGF-ß induced by high glucose and other agents in MC. Increased
generation of reactive oxygen species occurs in response to high glucose
and/or angiotensin II in MC and endothelial cells
(46,47).
There is evidence to indicate that high glucose and other stimuli signal
increases in TGF-ß and the subsequent increases in matrix protein
production by MC at least in part through activation of the protein kinase C
(PKC) system (45). In cultured
MC, several antioxidants as well as PKC inhibitors blocked the increases in
PKC, TGF-ß, and matrix protein synthesis induced by high glucose or
thromboxane but did not prevent increases in matrix protein synthesis in
response to exogenous TGF-ß
(45). Thus, suppression of the
activation of glomerular PKC that is known to occur in vivo in
diabetes mellitus (48) may
represent one mechanism by which antioxidants prevent increases in glomerular
TGF-ß and matrix protein synthesis in this disorder.
The present studies were not specifically designed to establish the
efficacy or potency of LA versus VC or VE in the prevention of
diabetic renal injury, but they nevertheless suggest that LA may be relatively
more effective than either VE or VC in this regard. Results of our current and
earlier studies (21) with VE
and VC indicate that the actions of the last two agents are dose related and
that very high doses are required to modify indices of glomerular injury in
the STZ-diabetic rat. In the present study, the lowest oral dose of VE that
detectably increased (by 30%) renal cortical levels of the vitamin in the
diabetic rats was used. This represented a 20-fold increase in dietary VE
consumption compared with diabetic rats that received a standard diet. At this
relatively high dose, VE supplementation failed to attenuate albuminuria or
the increases in VG, glomerular TGF-ß, and collagen 1
(IV) accumulation. Moreover, a twofold higher dose of VE, which represented a
40-fold increase in dietary VE consumption and raised renal cortical VE levels
approximately 60%, attenuated but did not totally prevent increases in
VG or glomerular TGF-ß content in the STZ-diabetic rat. This
higher dose also failed to prevent the development or alter the magnitude of
UAE in the diabetic rats (21).
Thus, even extremely high levels of dietary VE consumption only partially
ameliorated parameters of early renal injury in the STZ-diabetic rat.
Similarly, the dose of VC used in the present study that increased renal
cortical levels of VC twofold suppressed UAE and increases in VG in
the diabetic rats but did not prevent glomerular accumulation of TGF-ß or
collagen IV. A 10-fold higher dose of VC (fivefold increase in renal cortical
VC) was required to suppress glomerular TGF-ß
(21). By contrast to VC and
VE, LA suppressed all indices of early glomerular injury in the diabetic rats
to values not different from those in nondiabetic rats. The dose of LA used is
at the low end of the range (25 to 100 mg/kg body wt per d) previously
reported to attenuate peripheral nerve injury in the STZ-diabetic rats
(28,30).
These observations indicate that LA is highly effective in preventing renal
injury in diabetes mellitus and in particular in the suppression of increases
in glomerular and tubular TGF-ß and glomerular matrix protein
accumulation. LA may be more potent than either VE or VC in these actions.
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Acknowledgments |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-Lipoic acid increases
intracellular glutathione in a human T-lymphocyte Jurkat cell line.Biochem Biophys Res Commun
207:258
-264, 1995[Medline]
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